Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Cancer Cell. 2021 Jan 11;39(1):68-82.e9. doi: 10.1016/j.ccell.2020.10.012. Epub 2020 Nov 12.

Abstract

Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.

Keywords: FGF1; GDF-15; MMPs; PTEN; TIMP1; docetaxel; prostate cancer metastasis; senescence; senescence-associated secretory phenotype (SASP); senolytic therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Senescence / drug effects
  • Docetaxel / administration & dosage*
  • Docetaxel / pharmacology
  • Gene Deletion*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • PC-3 Cells
  • PTEN Phosphohydrolase / genetics*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*

Substances

  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Docetaxel
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Matrix Metalloproteinases